Entry Detail
| General information | |
| Database: | DB00476 |
| Objective: | Vatalanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), whereas everolimus inhibits mammalian target of rapamycin (mTOR). Combination therapy with VEGFR and mTOR inhibitors has not been well tolerated to date but may have efficacy in renal cell carcinoma (RCC). |
| Authors: | Bitting RL, et al |
| Title: | a phase Ib study of combined VEGFR and mTOR inhibition with vatalanib and everolimus in patients with advanced renal cell carcinoma. |
| Journal: | Clin Genitourin Cancer |
| Year: | 2014 |
| PMID: | 24685058 |
| Trial Design | |
| Clinical Trial Id: | NA |
| Agent: | everolimus+ vatalanib |
| Target: | Vascular endothelial growth factor receptor 3 Vascular endothelial growth factor receptor 2 Epidermal growth factor receptor mRNA of VEGFR1 |
| Cancer Type: | renal cell carcinoma |
| Cancer Subtype: | advanced renal cell carcinoma |
| Therapy Type: | com |
| Therapeutic Combination Type: | 1 |
| Therapeutic Combination Content: | vatalanib + everolimus |
| Study Type: | a singlearm, openlabelphase Ib trial |
| Key Patients Feature: | Patients eligible for this study included adults (more than and equal to 18 years) with histologically confirmednonhematologic malignancy and radiographically measurable metastatic disease for whichthere is no standard therapy. For patients with prostate cancer, biochemical evidence of disease (ie, elevated prostatespecific antigen [PSA]) in the setting of nonmeasurable bonemetastases was allowed. patients were required to have good performance status (Karnofskyperformance status more than and equal to 70) and acceptable bone marrow, kidney, and liver function (absoluteneutrophil count more than and equal to 1500/mm3, platelet count more than and equal to 100, 000/mm3, hemoglobin value more than and equal to 9 g/dL, creatinine clearance > 40 mL/min, bilirubin level less than and equal to 1.5 times the upper limit of normal, andaspartate aminotransferase and alanine aminotransferase levels less than and equal to 2.5 times the upper limit ofnormal). Total cholesterol was required to be < 300 mg/dL and triglyceride levels < 350mg/dL. Previous chemotherapy (> 4 weeks; > 6 weeks for mitomycin C, nitrosureas, orantibody therapy), radiotherapy, biological/immunotherapy or surgery (> 4 weeks) werepermitted provided that there was resolution of all toxicities of Common TerminologyCriteria for Adverse Events grade less than and equal to 1 |
| Biomarker: | NA |
| Biomark Analysis: | NA |
| Control Group Info: | single arm |
| Treatment Info: | The dose escalation portion assessed the combination of vatalanib and everolimus; Each drug was given on a daily oral schedule, with escalation of vatalanib in 250mg increments from 1000 to 1500 mg (3 patients per cohort) and everolimus at 5 mg or 10 mg. Vatalanib was begun on day 1 of the 28day cycle, whereas everolimus was begun on day 15 to allow assessment of vatalanib pharmacokinetics at steady state, both alone and in combination with everolimus. |
| Primary End Point: | maximum tolerated dose (MTD), safety, and tolerability of the combination |
| Secondary End Point: | NA |
| Patients Number: | 32 |
| Trial Results | |
| DLT_MTD: | The most common toxicities of any grade were proteinuria, fatigue, hypertriglyceridemia, nausea, and vomiting. Doselimiting toxicities (DLTs) included severe hypertension, diarrhea, neutropenia, mucositis, and fatigue. The MTD for the combination was vatalanib 1000 mg daily and everolimus 5 mg daily. |
| Objective Response Rate: | Tumor response by RECIST criteria was seen in individual patients with various solid tumor types. For instance, confirmed partial responses were seen in patients with pancreatic neuroendocrine cancer (n = 1), pancreatic adenocarcinoma (n = 1), and RCC (n = 5). Several additional patients demonstrated long periods of stable disease (> 4 months) with minor tumor regressions. Two of 4 patients with metastatic castrationresistant, chemotherapyrefractory prostate cancer demonstrated stable disease for > 6 months with minor PSA reduction. Tumor responses were seen at all dosing levels. |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | In patients with RCC, median progression free survival (PFS) was 5.8 months |
| Median OS A vs. C: | In all patients: 16.3 months. In patients with RCC, OS was 16.5 months |
| Adverse Event(agent arm): | The most common toxicities of any grade were proteinuria, fatigue, hypertriglyceridemia, nausea, and vomiting. Doselimiting toxicities (DLTs) included severe hypertension, diarrhea, neutropenia, mucositis, and fatigue. |
| Conclusions: | Relevant doses of vatalanib and everolimus they were achieved in combination, with expected toxicities. A substantial number of patients with RCC achieved an objective response in the treatmentnaive setting, with prolonged tolerability and survival. Further comparativephase IIIII studies of specifically targeted VEGF and mTOR inhibitor combinations may be warranted in patients with RCC. |